When subjected to induced high fever, tumor cells undergo drastic changes, often culminating in cell death. Our goal has been to achieve a better understanding of key events leading to cell death via hyperthermia, as a correct understanding of the process may allow one to "trick" cellular regulatory mechanisms so that it can help destroy tumor cells more effectively with minimum harm to the surrounding normal tissues. Success with radiation-heat combinations has been attributed to the heat sensitivity of hypoxic tumor cells which are otherwise radioresistant. The heat sensitivity of hypoxic cells in turn, has been explained in terms of the large (two orders of magnitude) amplification of the heat effect by low pH which hypoxia produces. Our immediate aim is to understand the potentiation of hyperthermia by low pH and to apply this understanding in improving hyperthermia therapy. Since many tumor cells maintain a normal growth at a media pH of 6.7 and a temperature of 37 C, it is hyperthermia that results in cells becoming sensitive to low media pH. Evidence suggests that the loss of K ions and the gain of H ions might be responsible for the cellular sensitivity to low pH during hyperthermia. In order to reinforce this theory, it is proposed here to study the potentiation of hyperthermia by nigericin which exchanges H for K ions. The shift of the survival curves will be investigated as nigericin is introduced. The indicators of vital cellular functions will also be monitored with the cellular content of K ions and pH. The action of nigericin on the mitochondria and on the plasma membrane will be separated by employing anaerobically grown tumor cells. When tumor cells are heated at normal pH, they also lose K and Cl ions and gain hydrogen ions. The driving force appears to be the accumulation of amino acids. The source of this excess amino acids will be found. The cells accumulating amino acids would be, in effect, immersed in a hyposmolar media unless they remove their excess osmolarity instantly. The loss of K and chloride (Cl) ions and the gain of H ions by heated cells are, thus, analogous to the ionic transaction known as "Volume Regulatory Decrease" which cells placed in hyposmolar solutions undergo. One can test this hypothesis by the following two methods: removing a portion or all of amino acids in the media during hyperthermia, which should block both the swelling and the decrease in the cell K and Cl; and secondly, demonstrating that the KCl loss is blocked by K rich isosmolar media as the theory predicts.